Commensal Microbiota and CD8+ T Cells Shape the Formation of Invariant NKT Cells

Abstract

Commensal bacteria play an important role in formation of the immune system, but the mechanisms involved are incompletely understood. In this study, we analyze CD1d-restricted invariant NKT (iNKT) cells in germfree mice and in two colonies of C57BL/6 mice termed conventional flora and restricted flora (RF), stably bearing commensal microbial communities of diverse but distinct composition. In germfree mice, iNKT cells were moderately reduced, suggesting that commensal microbiota were partially required for the antigenic drive in maintaining systemic iNKT cells. Surprisingly, even greater depletion of iNKT cell population occurred in RF mice. This was in part attributable to reduced RF levels of intestinal microbial taxa (Sphingomonas spp.) known to express antigenic glycosphingolipid products. However, memory and activated CD8+ T cells were also expanded in RF mice, prompting us to test whether CD8+ T cell activity might be further depleting iNKT cells. Indeed, iNKT cell numbers were restored in RF mice bearing the CD8α−/− genotype or in adult wild-type RF mice acutely depleted with anti-CD8 Ab. Moreover, iNKT cells were restored in RF mice bearing the Prf1−/− phenotype, a key component of cytolytic function. These findings indicate that commensal microbiota, through positive (antigenic drive) and negative (cytolytic depletion by CD8+ T cells) mechanisms, profoundly shape the iNKT cell compartment. Because individuals greatly vary in the composition of their microbial communities, enteric microbiota may play an important epigenetic role in the striking differences in iNKT cell abundance in humans and therefore in their potential contribution to host immune status.

Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction

“…Supporting a possible role for oral lipid antigens, two studies have used orally-administered α-galactosylceramide as a vaccine adjuvant, and both studies reported a measureable result with oral administration (35,36). Studies of lipid antigens from commensal bacteria also support a role for lipids antigens in the digestive system (29,30,37,38). Our studies demonstrate reactivity of human iNKT cells to a component of the GlcCer-enriched lipid fraction from human milk, cow's milk, and soy milk.…”

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

“…The reason for this lack of correlation between murine and human data remains unclear; one possibility is that it is due to the different enteric microbiome occurring in human and in experimental animals, a variable that can shape iNKT and MAIT cell populations (13,37). The difference also raises the question whether murine iNKT and human MAIT cells perform similar effector functions.…”

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

“…Similar findings have been reported in animal studies. For example, in GF mice and those in the first days of colonization smaller Peyer's patches and low level cellularity of the lamina propria and low Cd4 + and Cd8 + T cells are reported (Wei et al, 2010;El Aidy et al, 2012). Furthermore, intraepithelial lymphocytes and plasma cells are rare in the small intestinal mucosa while secretory immunoglobulin A (sIgA) levels are significantly lower with suppressed expression of genes and markers of activation for intestinal macrophages (Mikkelsen et al, 2004;El Aidy et al, 2012).…”